Yuan Xiaotian, Liu Tiantian, Xu Dawei
School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China.
Department of Medicine, Division of Hematology, Bioclinicum and Center for Molecular Medicine (CMM), Karolinska Institutet and Karolinska University Hospital Solna, Solna, Sweden.
Ann Transl Med. 2020 Oct;8(19):1244. doi: 10.21037/atm-20-5024.
Telomerase is a ribonucleoprotein enzyme with telomerase reverse transcriptase (TERT) as a catalytic component. In normal human follicular thyroid cells or thyrocytes, telomerase is silent due to the gene being tightly repressed. However, during the formation of thyroid carcinoma (TC), telomerase becomes activated via TERT induction. The TERT promoter's gain-of-function mutation has recently been identified in TCs and many other malignancies. The mutation creates a ETS-binding motif through which TERT transcription is de-repressed and telomerase is activated; through this, the mutant TERT promoter promotes the development of TC, contributes to disease aggressiveness and treatment resistance, and thereby leads to poor patient outcomes. From a clinical point of view, the strong association between the TERT promoter mutation and disease malignancy and aggressiveness holds great promise for its value in TC diagnostics, risk stratification, prognostication, treatment decision, and follow-up design. In the present review article, we summarize the recent findings of studies of TERT promoter mutations in TC and underscore the implications of TERT hyperactivity driven by genetic events in the pathogenesis and management of TC. Finally, the targeting of TERT promoter mutations and the disruption of telomere maintenance are considered as potential therapeutic strategies against TC.
端粒酶是一种核糖核蛋白酶，其催化成分是端粒酶逆转录酶（TERT）。在正常人类甲状腺滤泡细胞或甲状腺细胞中，由于基因被严格抑制，端粒酶处于沉默状态。然而，在甲状腺癌（TC）形成过程中，端粒酶通过TERT诱导而被激活。最近在甲状腺癌和许多其他恶性肿瘤中发现了TERT启动子的功能获得性突变。该突变产生一个ETS结合基序，通过该基序TERT转录被解除抑制，端粒酶被激活；通过这种方式，突变的TERT启动子促进甲状腺癌的发展，导致疾病侵袭性和治疗耐药性，从而导致患者预后不良。从临床角度来看，TERT启动子突变与疾病恶性程度和侵袭性之间的强关联使其在甲状腺癌诊断、风险分层、预后评估、治疗决策和随访设计方面具有很大价值。在本综述文章中，我们总结了甲状腺癌中TERT启动子突变研究的最新发现，并强调了由遗传事件驱动的TERT过度活跃在甲状腺癌发病机制和管理中的意义。最后，靶向TERT启动子突变和破坏端粒维持被认为是针对甲状腺癌的潜在治疗策略。
